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Journal Article

Enhanced dimerization drives ligand-independent activity of mutant EGFR in lung cancer.


Arndt-Jovin,  D. J.
Emeritus Group Laboratory of Cellular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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(Supplementary material), 7MB

(Supplementary material), 5MB


Valley, C. C., Arndt-Jovin, D. J., Karedla, N., Steinkamp, M. P., Chizhik, A. I., Hlavacek, W. S., et al. (2015). Enhanced dimerization drives ligand-independent activity of mutant EGFR in lung cancer. Molecular Biology of the Cell, 26(22), 4087-4099. doi:10.1091/mbc.E15-05-0269.

Cite as: http://hdl.handle.net/11858/00-001M-0000-0028-935A-3
Mutations within the epidermal growth factor receptor (EGFR/erbB1/Her1) are often associated with tumorigenesis. In particular, a number of EGFR mutants that demonstrate ligand-independent signaling are common in non-small cell lung cancer (NSCLC), including kinase domain mutations L858R (also called L834R) and exon 19 deletions (e.g. ΔL747-P753insS) which collectively make up nearly 90% of mutations in NSCLC. The molecular mechanisms by which these mutations confer constitutive activity remain unresolved. Using multiple subdiffraction-limit imaging modalities, we reveal the altered receptor structure and interaction kinetics of NSCLC-associated EGFR mutants. We applied two-color single quantum dot tracking to quantify receptor dimerization kinetics on living cells and show that, in contrast to wild type EGFR, mutants are capable of forming stable, ligand-independent dimers. Two-color super-resolution localization microscopy confirmed ligand-independent aggregation of EGFR mutants. Live cell FRET measurements revealed that the L858R kinase mutation alters ectodomain structure such that unliganded mutant EGFR adopts an extended, dimerization-competent conformation. Finally, mutation of the putative dimerization arm confirmed a critical role for ectodomain engagement in ligand-independent signaling. These data support a model in which dysregulated activity of NSCLC-associated kinase mutants is driven by coordinated interactions involving both the kinase and extracellular domains that lead to enhanced dimerization.